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    Topic review

    Circulating Biomarkers of Colorectal Cancer

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    Definition

    Colorectal cancer (CRC) is one of the most common neoplasms worldwide. It is the second most frequently diagnosed malignancy in women and third in men. It is estimated that more than one million people worldwide develop CRC every year. In addition, this carcinoma is the second leading cause of cancer death in Europe, ranking fourth in males and third in females.

    1. Introduction

    The challenges facing medicine in the future lie in the establishment of new diagnostic strategies based on novel and accurate tumor biomarkers that will improve the early detection of malignant diseases, such as CRC, and facilitate differentiation between CRC and CA. A growing number of publications focus on the molecular and cellular mechanisms involved in the development, progression and metastasis of this malignancy. The design of epigenetic and genetic panels of biomarkers useful in CRC diagnosis constitutes a reasonable strategy in the clinical management of CRC [1][2][3]. There are three main mechanisms that are currently considered to be responsible for CRC pathogenesis. The first one is the suppressor pathway, or the pathway of chromosomal instability, which is associated with the accumulation of mutations leading to oncogene activation (KRAS) and suppressor gene inactivation (TP53, DCC, SMAD4, APC), and consequently to neoplastic transformation [4][5]. The second pathway is the accumulation of errors during DNA replication due to the presence of mutations in the genes responsible for its repair (MLH1, MSH2, MSH6, PMS2, MLH3, MSH3, PMS1 and Exo1) [6]. The third mechanism is related to aberrant hypermethylation [7].

    Many recent reports have focused on RAS, BRAF (Raf murine sarcoma viral oncogene homolog B) and HER2 (human epidermal growth factor receptor 2 gene) mutations as predictive factors of mCRC patients who receive chemotherapy [8][9]. A study by Zheng investigated the frequency and prognostic role of HER2 and BRAF gene mutations in CRC patients. The authors concluded that HER2 amplification significantly correlates with greater bowel wall invasion and a more advanced TNM stage, while HER2 amplification is an independent prognostic factor for worse disease-free survival [8]. Moreover, a statistically significant correlation for the RAS mutation and overall survival was also proved, whereas RAS mutation and liver metastasis were found to be independent factors for shorter overall survival of CRC patients in multivariate analysis [9].

    A greater understanding of the pathways involved in CRC development will facilitate the establishment of diagnostic and prognostic biomarkers for this malignancy. In recent years, DNA and RNA markers in blood have been investigated as a potential diagnostic tool in CRC. It has been indicated that the analysis of biomarkers, such as DNA, RNA or proteins in the blood, accelerates the development of diagnostic tools in molecular biology. These techniques are characterized by greater sensitivity and enhanced cost-effectiveness, and may be employed in clinical practice [1].

    2. DNA-Based Biomarkers

    A variety of DNA markers have been assessed in plasma, including APC, KRAS, p53, MLH1, HLTF, TMEF2, NGFR, and SEPT9 [1]. A study by Diehl et al., which utilized the detection of mutations by beads, emulsification, amplification and magnetics (BEAMing) assay, found that APC mutations in plasma samples were detected with a sensitivity of 73%, which, however, was limited to 9% in patients with CA [10]. Furthermore, some authors have demonstrated that the hypermethylation of Septine 9 (guanosine triphosphatase class gene) is related to CRC development [11][12] and is found in 58–96% of CRC patients, and in only 18% of CA subjects with specificities of 86–100% [11][12][13][14].

    3. RNA-Based Biomarkers

    Some clinical investigations have revealed that the transcriptome of plasma and peripheral blood also offers potential diagnostic biomarkers [15][16]. A plasma biomarker panel including BANK1, BCNP1, CDA, MGC20553 and MS4A1 may discriminate patients with CRC from healthy subjects with a sensitivity and specificity of 88% and 64%, respectively [15][16]. Other molecular biomarkers provide a source of miRNAs [17][18][19]. Elevated miR92 levels have been detected in the plasma of patients with CRC compared with healthy individuals [20]. Moreover, statistically higher levels of miR92a and miR29a have been found in patients with CRC and CA in comparison to healthy controls [21].

    4. Plasma Proteins

    The development of new technologies in proteomics, such as chromatographic techniques based on mass spectrometry (MS) assays, surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF)-MS, and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS, allows for the identification of large-scale protein patterns. These methods allow for the identification of peptide patterns that discriminate patients with CRC from healthy individuals with a sensitivity and specificity of 90% [22]. However, they are not specific to CRC [23]. Some authors have evaluated the significance of epithelial cell adhesion molecules, p53, p62, CEA, HER-2/neu, Ras, topoisomerase Ⅱ-alpha, histone deacetylase 3 and 5, ubiquitin L3, tyrosinase, tropomyosin, and cyclin B1 as biomarkers for CRC. These stable biomarkers can be detected by immunoassays and are absent in healthy individuals, and therefore might be promising biomarkers for further research [1][24][25][26]. Moreover, some clinical investigations have assessed the combined ELISA analysis of MAPKAPK3 and ACVR2B in patients with CRC and healthy controls, with a sensitivity of 83% and a specificity of 74% [25][27].

    Although there is still insufficient evidence supporting the use of biomarkers, such as genetic and epigenetic biomarker panels in CRC diagnosis, it appears to be a reasonable strategy for the medicine of the future [1]. However, what should also be taken into consideration is that CRC cells are able to enter blood via blood vessel invasion, where they circulate and release detectable biomarkers in the plasma or circulating phagocytes. Furthermore, such vessel invasion occurs more frequently in the advanced stages of CRC [28][29][30].

    The entry is from 10.3390/jcm10112391

    References

    1. Binefa, G.; Rodríguez-Moranta, F.; Teule, A.; Medina-Hayas, M. Colorectal cancer: From prevention to personalized medicine. World J. Gastroenterol. 2014, 20, 6786–6808.
    2. Ogunwobi, O.O.; Mahmood, F.; Akingboye, A. Biomarkers in Colorectal Cancer: Current Research and Future Prospects. Int. J. Mol. Sci. 2020, 21, 5311.
    3. Marcuello, M.; Vymetalkova, V.; Neves, R.P.; Duran-Sanchon, S.; Vedeld, H.M.; Tham, E.; van Dalum, G.; Flügen, G.; Garcia-Barberan, V.; Fijneman, R.J.; et al. Circulating biomarkers for early detection and clinical management of colorectal cancer. Mol. Asp. Med. 2019, 69, 107–122.
    4. Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767.
    5. Rustgi, A.K. Hereditary Gastrointestinal Polyposis and Nonpolyposis Syndromes. N. Engl. J. Med. 1994, 331, 1694–1702.
    6. Boland, C.R.; Sinicrope, F.A.; Brenner, D.E.; Carethers, J.M. Colorectal cancer prevention and treatment. Gastroenterology 2000, 118, S115–S128.
    7. Weisenberger, D.J.; Siegmund, K.D.; Campan, M.; Young, J.; Long, T.I.; Faasse, M.A.; Kang, G.H.; Widschwendter, M.; Weener, D.; Buchanan, D.; et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 2006, 38, 787–793.
    8. Zhang, X.; Wu, J.; Wang, L.; Zhao, H.; Li, H.; Duan, Y.; Li, Y.; Xu, P.; Ran, W.; Xing, X. HER2 and BRAF mutation in colorectal cancer patients: A retrospective study in Eastern China. PeerJ 2020, 8, e8602.
    9. Osumi, H.; Shinozaki, E.; Suenaga, M.; Matsusaka, S.; Konishi, T.; Akiyoshi, T.; Fujimoto, Y.; Nagayama, S.; Fukunaga, Y.; Ueno, M.; et al. RAS mutation is a prognostic biomarker in colorectal cancer patients with metastasectomy. Mol. Cancer Biol. 2016, 139, 803–811.
    10. Diehl, F.; Li, M.; Dressman, D.; He, Y.; Shen, D.; Szabo, S.; Diaz, L.A.; Goodman, S.N.; David, K.A.; Juhl, H.; et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc. Natl. Acad. Sci. USA 2005, 102, 16368–16373.
    11. Devos, T.; Tetzner, R.; Model, F.; Weiss, G.; Schuster, M.; Distler, J.; Steiger, K.V.; Grützmann, R.; Pilarsky, C.; Habermann, J.K.; et al. Circulating Methylated SEPT9 DNA in Plasma Is a Biomarker for Colorectal Cancer. Clin. Chem. 2009, 55, 1337–1346.
    12. Mullard, A. Alnylam dealt blow. Nat. Biotechnol. 2009, 27, 213.
    13. Grützmann, R.; Molnar, B.; Pilarsky, C.; Habermann, J.K.; Schlag, P.M.; Saeger, H.D.; Miehlke, S.; Stolz, T.; Model, F.; Roblick, U.J.; et al. Sensitive Detection of Colorectal Cancer in Peripheral Blood by Septin 9 DNA Methylation Assay. PLoS ONE 2008, 3, e3759.
    14. Lofton-Day, C.; Model, F.; Devos, T.; Tetzner, R.; Distler, J.; Schuster, M.; Song, X.; Lesche, R.; Liebenberg, V.; Ebert, M.; et al. DNA Methylation Biomarkers for Blood-Based Colorectal Cancer Screening. Clin. Chem. 2008, 54, 414–423.
    15. Liew, C.-C.; Ma, J.; Tang, H.-C.; Zheng, R.; Dempsey, A.A. The peripheral blood transcriptome dynamically reflects system wide biology: A potential diagnostic tool. J. Lab. Clin. Med. 2006, 147, 126–132.
    16. Han, M.; Liew, C.T.; Zhang, H.W.; Chao, S.; Zheng, R.; Yip, K.T.; Song, Z.Y.; Li, H.M.; Geng, X.P.; Zhu, L.X.; et al. Novel blood-based, five-gene biomarker set forthe detection of colorectal cancer. Clin. Cancer Res. 2008, 14, 455–460.
    17. Chen, X.; Ba, Y.; Ma, L.; Cai, X.; Yin, Y.; Wang, K.; Guo, J.; Zhang, Y.; Chen, J.; Guo, X.; et al. Characterization of microRNAs in serum: A novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008, 18, 997–1006.
    18. Aslam, M.I.; Taylor, K.; Pringle, J.H.; Jameson, J.S. MicroRNAs are novel biomarkers of colorectal cancer. BJS 2009, 96, 702–710.
    19. Mostert, B.; Sieuwerts, A.M.; Martens, J.W.M.; Sleijfer, S. Diagnostic applications of cell-free and circulating tumor cell-associated miRNAs in cancer patients. Expert Rev. Mol. Diagn. 2011, 11, 259–275.
    20. Ng, E.K.-O.; Chong, W.W.S.; Jin, H.; Lam, E.K.Y.; Shin, V.Y.; Yu, J.; Poon, T.C.W.; Ng, S.S.M.; Sung, J.J.Y. Differential expression of microRNAs in plasma of patients with colorectal cancer: A potential marker for colorectal cancer screening. Gut 2009, 58, 1375–1381.
    21. Huang, Z.; Huang, D.; Ni, S.; Peng, Z.; Sheng, W.; Du, X. Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int. J. Cancer 2009, 127, 118–126.
    22. Hundt, S.; Haug, U.; Brenner, H. Blood Markers for Early Detection of Colorectal Cancer: A Systematic Review. Cancer Epidemiol. Biomark. Prev. 2007, 16, 1935–1953.
    23. Wang, Q.; Shen, J.; Li, Z.-F.; Jie, J.-Z.; Wang, W.-Y.; Wang, J.; Zhang, Z.-T.; Li, Z.-X.; Yan, L.; Gu, J. Limitations in SELDI-TOF MS whole serum proteomic profiling with IMAC surface to specifically detect colorectal cancer. BMC Cancer 2009, 9, 287.
    24. Kobold, S.; Luetkens, T.; Cao, Y.; Bokemeyer, C.; Atanackovic, D. Prognostic and Diagnostic Value of Spontaneous Tumor-Related Antibodies. Clin. Dev. Immunol. 2010, 2010, 1–8.
    25. Casal, J.I.; Barderas, R. Identification of cancer autoantigens in serum: Toward diagnostic/prognostic testing? Mol. Diagn. Ther 2010, 14, 149–154.
    26. Lu, H.; Goodell, V.; Disis, M.L. Targeting serum antibody for cancer diagnosis: A focus on colorectal cancer. Expert Opin. Ther. Targets 2007, 11, 235–244.
    27. Babel, I.; Barderas, R.; Diaz-Uriarte, R.; Martínez-Torrecuadrada, J.L.; Sánchez-Carbayo, M.; Casal, J.I. Identification of Tumor-associated Autoantigens for the Diagnosis of Colorectal Cancer in Serum Using High Density Protein Microarrays. Mol. Cell. Proteom. 2009, 8, 2382–2395.
    28. Stetler-Stevenson, W.G.; Aznavoorian, S.; Liotta, L.A. Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis. Annu. Rev. Cell Biol. 1993, 9, 541–573.
    29. Sastre, J.; Maestro, M.L.; Puente, J.; Veganzones, S.; Alfonso, R.; Rafael, S.; García-Saenz, J.A.; Vidaurreta, M.; Martín, M.; Arroyo, M.; et al. Circulating tumor cells in colorectal cancer: Correlation with clinical and pathological variables. Ann. Oncol. 2008, 19, 935–938.
    30. Tsouma, A.; Aggeli, C.; Pissimissis, N.; Lembessis, P.; Zografos, G.N.; Koutsilieris, M. Circulating tumor cells in colorectal cancer: Detection methods and clinical significance. Anticancer Res. 2009, 28, 3945–3960.
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